Alzheimer's Disease is a progressive dementia in which massive deposits of aggregated protein breakdown products (β-amyloid plaques and neurofibrillary tangles) accumulate in the brain, resulting in the loss of memory, cognition, reasoning, judgement, orientation, and eventually death. Current therapies for the treatment of Alzheimer's Disease include, but are not limited to, donepezil and tacrine. These therapies are useful for improving the memory of patients during the early stages of Alzheimer's Disease, however they do not modify the progression of aggregated protein breakdown products underlying the pathology of Alzheimer's Disease. It would be desirable to develop therapies that would either stop or slow down this process of aggregation.
As described above, a defining feature of Alzheimer's Disease which is often used during clinical diagnosis is the presence of β-amyloid plaques and neurofibrillary tangles. β-amyloid plaques are predominantly composed of amyloid β peptide (Aβ (or βA4), which is derived by proteolysis of the amyloid precursor protein (APP). Proteolysis of the amyloid precursor protein is effected by several enzymes called secretases. More specifically, cleavage of APP at the N-terminus of the Aβ peptide by β-secretase and at the C-terminus by one or more γ-secretases constitutes the β-amyloidogenic pathway, i.e., the pathway by which Aβ is formed. It is believed that Aβ peptide accumulates as a result of this APP processing by β-secretase and thus inhibition of this enzyme's activity is desirable for the treatment of Alzheimer's Disease. For example, in vivo processing of APP at the β-secretase cleavage site is thought to be a rate limiting step in Aβ production, and is thus believed to be a therapeutic target for Alzheimer's Disease (Sabbagh et al. Alz. Dis. Rev. 1997, 3, 1–19). Recently, an aspartyl protease (known as BACE, Asp2, Memapsin) has been identified as the enzyme responsible for processing of APP at the β-secretase cleavage site (see, for example, Vassar, et al. Science, 1999, 286, 735–741; Yan et al. Nature, 1999, 402, 533–537; Sinha et al. Nature, 1999, 402, 537–540; and Hussain et al. Mol. Cell. Neurosci. 1999, 14, 419–427).
Because it is believed that BACE plays an important role in the development and pathogenesis of Alzheimer's Disease, there has been increasing interest in the development of inhibitors of BACE as treatments (and possibly as preventative agents) for Alzheimer's Disease and other disorders caused by the accumulation of β-amyloid plaques. There remains a need, however, for the development of novel therapeutics capable of inhibiting the activity of this aspartyl protease. In particular, it would be desirable to develop therapeutics capable of selectively inhibiting BACE.